Home > Neurology > AAN 2023 > Positive results for hereditary transthyretin-mediated amyloid polyneuropathy

Positive results for hereditary transthyretin-mediated amyloid polyneuropathy

Prof. Sami Khella, University of Pennsylvania, PA, USA
AAN 2023
Phase 3, NEURO-TTRansform
Prof. Sami Khella (University of Pennsylvania, PA, USA) and colleagues presented both the 35 and 66-week data from the NEURO-TTRansform study (NCT04136184) at the American Academy of Neurology (AAN) Annual Meeting in April 2023 [1,2]. This phase 3 clinical trial asks whether an investigational antisense drug called eplontersen provides benefit for people living with hereditary transthyretin-mediated amyloid polyneuropathy. In this study, eplontersen met co-primary endpoints demonstrating a sustained reduction in transthyretin (TTR) and benefits in neuropathy and quality of life through 66 weeks.


Hereditary transthyretin-mediated amyloid polyneuropathy is caused by the accumulation of misfolded mutated TTR protein in the peripheral nerves. Patients with this disease experience ongoing debilitating nerve damage throughout their body resulting in the progressive loss of motor functions, such as walking. These patients also accumulate TTR in other major organs, which progressively compromises their function. The damage from misfolded TTR protein accumulation leads to disability within 5 years of diagnosis and is generally fatal within a decade.

Medicom interviewed Prof. Khella about the results of the phase 3 NEURO-TTRansform study and the impact they have on clinical practice.

Prof. Khella explained to us what the unmet need is for patients with transthyretin-mediated amyloidosis. “The basic unmet need is early diagnosis,” he said. “This is a rare disorder which is difficult to diagnose when it starts because it looks like other, more common, disorders. Only as the patient progresses and becomes more affected by the disease it becomes apparent that this patient could have amyloidosis. For that reason, practitioners should be more aware of it. On the other hand, it's difficult to be constantly thinking of a rare disorder because you don't see a lot of it.”

Next, Prof. Khella provided the overall idea behind the phase 3 NEURO-TTRansform Study “The basic idea is that the study drug eplontersen showed that it is effective at reducing the progression of amyloid polyneuropathy of the hereditary type, just like the FDA-approved sister drug inotersen,” he explained. “At 66 weeks, the phase 3 NEURO-TTRansform trial demonstrated that there was a reduction in the progression of the neuropathy associated with the hereditary amyloidosis in patients receiving eplontersen compared with historical controls that were used in the pivotal trial that assessed inotersen. The placebo arm was used as a control arm in this open-label trial. Also, the research team compared eplontersen with inotersen in a small group of patients.” Both drugs performed better than placebo, which is very exciting news, according to Prof. Khella.

“One important difference between the 2 agents is that the new drug eplontersen is given on a monthly basis as an injection, whereas inotersen was initially administered weekly,” he continued. “The rationale behind eplontersen is to administer smaller doses because this drug targets the liver cells directly. It targets the liver cells because transthyretin, the protein that misfolds and becomes amyloidogenic, is mostly made in the liver. Therefore, by targeting the liver directly you can use a smaller amount of drug, get the same amount of transthyretin reduction but with fewer side effects.” Prof. Khella explained that the neuropathy impairment score + 7 was the primary endpoint of the study. “This is basically a quantification of the neurologic examination that all neurologists do in the office. The ‘+ 7’ comprises some additional autonomic testing, which is part and parcel of this illness as well. The primary endpoint was met with robust statistical significance.” Prof. Khella added that thrombocytopaenia is the main side effect of inotersen. “This side effect can easily be controlled by careful monitoring of the platelet count,” he said. “Once one is cognisant of the platelet count, you can detect dropping platelet counts and subsequently stop the administration of the drug or do other things to allow the platelet count to come back up.”

Prof. Khella outlined that the results of this trial will have a great impact on clinical practice.

“I think this is going to be huge. First of all, as most of the readers probably know, amyloidosis is a progressive, debilitating, and ultimately fatal disease. Until recently, there had been no effective therapies. Now there are 3 FDA-approved agents targeting peripheral neuropathy and 1 approved agent targeting cardiomyopathy, which is called tafamidis [3]. These drugs clearly outperform placebo. Furthermore, in the placebo arms, we can observe that amyloidosis is a very progressive illness that causes fatal heart failure or severe peripheral neuropathy, affecting patients’ quality of life and daily functioning. “The benefit of these agents is going to be a greatly improved or at least stabilised quality of life.” Prof. Khella stressed that providers can be most helpful to patients by being vigilant of the disease. “In this way, they may diagnose the disease early, before it has caused irreversible damage.”

Finally, Prof. Khella pointed out that it is important to be careful with respect to applying these findings to other diseases. “I think that these novel drugs will mainly be applied in hereditary amyloidosis, obviously. However, trials like these are not going to capture all of the 130 different variants of the disease.” Therefore, it is currently unknown whether these agents will be equally effective in uncommon variants of the disease.

Next to the 130 different point mutations that have been described, there are variants of unknown significance. “This is a variant that has not been confirmed to cause a particular illness. However, as more people are tested, some variants of unknown significance turn out to be pathogenic. Therefore, it's important to follow up with patients with variants of unknown significance and keep them in mind.”

    1. Qarni T et al, Treatment characteristics in a cohort of patients with hereditary transthyretin amyloidosis. S7 - Neuromuscular and Clinical Neurophysiology (EMG) 1, AAN 2023, 23 April, Boston, USA.
    2. Coelho T, et al. Neurol Ther. 2023;12(1):267–287.
    3. Maurer MS, et al. N Engl J Med 2018;379(11):1007–1016.

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